Stem Cells and Cardiovascular Repair: We propose a comprehensive program on myocardial infarct repair using adult and pluripotent human stem cells, with an emphasis on pre-clinical translation. There are 3 projects and 3 cores. Project 1 (Murry, Schwartz, Mahoney) focuses on vascularization, beginning with transplants of clinically relevant sources of human cardiomyocytes, endothelium and MSCs. Next, they transplant a multipotent human cardiovascular progenitor from ESCs, capable of generating cardiomyocytes, endothelium and smooth muscle, to generate vascularized myocardium in the infarct. Finally, they explore mechanisms through which grafts induce collateral arterialization from the host coronaries. Project 2 (Laflamme, Santana) studies the electro-physiology of human cardiomyocytes, using genetic selection to generate pacemaker vs. working-type cells. They will identify signaling pathways that specify hESC-derived myocytes into working-type vs. pacemaker phenotypes, with a goal of determining if pacemaker cells are precursors of the working-type cells or a separate stable branch. Lastly, they use cell transplantation to assess the ability of the different myocyte subtypes to couple with host cardiomyocytes and test their differential effects on electrical stability. Project 3 (Torok-Storb, Bowen-Pope) develops a pre-clinical model in the dog for cardiac repair. They will generate a system for scalable production of cardiomyocytes from their recently generated canine induced pluripotent stem cells (iPSCs). Next, they investigate if MSCs can pro-mote repair by endogenous cells and exogenous cardio-myocytes, including testing if MSCs induce third-party tolerance to allogeneic cardiomyocytes. Finally, they perform transplantation studies with canine iPSC-derived cardiomyocytes and MSCs, creating a clinically relevant model of cardiac stem cell therapy in the dog. Projects are supported by a Stem Cell Core (A) that trains investigators in hESC use and provides differentiated cells i.e., cardiomyocytes; an Out-comes Core (B) provides histology services, a central source of expertise in animal models of myocardial infarction, cell transplantation and physiological assessment; and an Administrative Core (C) to coordinate meetings, seminar series, provide fiscal support and plan the annual PPG retreat.